Concurrent scanning non-invasive analysis system

ABSTRACT

A non-invasive imaging and analysis system suitable for measuring concentrations of specific components, such as blood glucose concentration and suitable for non-invasive analysis of defects or malignant aspects of targets such as cancer in skin or human tissue, includes an optical processing system which generates a probe and composite reference beam. The system also includes a means that applies the probe beam to the target to be analyzed and modulates at least some of the components of the composite reference beam by means of a micro-mirror array, such that signals corresponding to different depths within the target can be separated by electronic processing. The system combines a scattered portion of the probe beam and the composite beam interferometrically to concurrently acquire information from multiple depths within a target. It further includes electronic control and processing systems.

CROSS REFERENCES TO RELATED APPLICATIONS

This application, docket number JH050818US1, is a continuation in partof U.S. utility application Ser. No. 11/025,698 filed on Dec. 29, 2004titled “Multiple reference non-invasive analysis system”, the contentsof which are incorporated by reference as if fully set forth herein.This application, docket number JH050818US1, claims priority fromprovisional application Ser. No. 60/602,913 filed on Aug. 19, 2004titled “Multiple reference non-invasive analysis system”. Thisapplication also relates to U.S. utility application Ser. No. 10/949,917filed on Sep. 25, 2004 titled “Compact non-invasive analysis system”,the contents of which are incorporated by reference as if fully setforth herein. This application also relates to U.S. utility patentapplication Ser. No. 10/870,121 filed on Jun. 17, 2004 titled “ANon-invasive Analysis System”, the contents of which are incorporated byreference as if fully set forth herein. This application also relates toU.S. utility patent 10/870,120 filed on Jun. 17, 2004 titled “A RealTime Imaging and Analysis System”, the contents of which areincorporated by reference as if fully set forth herein.

FIELD OF THE INVENTION

The invention relates to non-invasive optical imaging and analysis andin particular to quantitative analysis of concentrations specificcomponents or analytes in a target. Such analytes include metabolites,such as glucose. This invention also relates to non-invasive imaging oranalysis of defects or malignant aspects of targets such as cancer inskin or human tissue.

BACKGROUND OF THE INVENTION

Non-invasive analysis is a valuable technique for acquiring informationabout systems or targets without undesirable side effects, such asdamaging the target or system being analyzed. In the case of analyzingliving entities, such as human tissue, undesirable side effects ofinvasive analysis include the risk of infection along with pain anddiscomfort associated with the invasive process.

In the particular case of measurement of blood glucose levels indiabetic patients, it is highly desirable to measure the blood glucoselevel frequently and accurately to provide appropriate treatment of thediabetic condition as absence of appropriate treatment can lead topotentially fatal health issues, including kidney failure, heart diseaseor stroke. A non-invasive method would avoid the pain and risk ofinfection and provide an opportunity for frequent or continuousmeasurement. Non-invasive glucose analysis based on several techniqueshave been proposed. These techniques include: near infrared spectroscopyusing both transmission and reflectance; spatially resolved diffusereflectance; frequency domain reflectance; fluorescence spectroscopy;polarimetry and Raman spectroscopy.

These techniques are vulnerable to inaccuracies due to issues such as,environmental changes, presence of varying amounts of interferingcontamination and skin heterogeneity. These techniques also requireconsiderable processing to de-convolute the required measurement,typically using multi-variate analysis. These techniques have heretoforeproduced insufficient accuracy and reliability to be clinically useful.

More recently optical coherence tomography (OCT), using asuper-luminescent diode (SLD) as the optical source, has been proposedin Proceedings of SPIE, Vol. 4263, pages 83-90 (2001). The SLD outputbeam has a broad bandwidth and short coherence length. The techniqueinvolves splitting the output beam into a probe and reference beam. Theprobe beam is applied to the system to be analyzed (the target). Lightscattered back from the target is combined with the reference beam toform the measurement signal.

Because of the short coherence length only light that is scattered froma depth within the target such that the total optical path lengths ofthe probe and reference are equal combine interferometrically. Thus theinterferometric signal provides a measurement of the scattering value ata particular depth within the target. By varying the length of thereference path length, a measurement of the scattering values at variousdepths can be measured and thus the scattering value as a function ofdepth can be measured.

The correlation between blood glucose concentration and the scatteringcoefficient of tissue has been reported in Optics Letters, Vol. 19, No.24, Dec. 15, 1994 pages 2062-2064. The change of the scatteringcoefficient correlates with the glucose concentration and thereforemeasuring the change of the scattering value with depth provides ameasurement of the scattering coefficient which provides a measurementof the glucose concentration. Determining the glucose concentration froma change, rather than an absolute value provides insensitivity toenvironmental conditions.

In conventional OCT systems depth scanning is achieved by modifying therelative optical path length of the reference path and the probe path.The relative path length is modified by such techniques aselectromechanical based technologies, such as galvanometers or movingcoils actuators, rapid scanning optical delay lines and rotatingpolygons. All of these techniques involve moving parts, which havelimited scan speeds and present significant alignment and associatedsignal to noise ratio related problems.

Motion occurring within the duration of a scan can cause significantproblems in correct signal detection. If motion occurs within a scanduration, motion related artifacts will be indistinguishable from realsignal information in the detected signal, leading to an inaccuratemeasurement. Long physical scans, for larger signal differentiation orlocating reference areas, increase the severity of motion artifacts.Problematic motion can also include variation of the orientation of thetarget surface (skin) where small variations can have significanteffects on measured scattering intensities.

Non-moving part solutions, include acousto-optic scanning, can be highspeed, however such solutions are costly, bulky and have significantthermal control and associated thermal signal to noise ratio relatedproblems.

Optical fiber based OCT systems also use piezo electric fiberstretchers. These, however, have polarization rotation related signal tonoise ratio problems and also are physically bulky, are expensive,require relatively high voltage control systems and also have the motionrelated issues. These aspects cause conventional OCT systems to havesignificant undesirable signal to noise characteristics and presentproblems in practical implementations with sufficient accuracy,compactness and robustness for commercially viable and clinicallyaccurate devices.

Therefore there is an unmet need for commercially viable, compact,robust, non-invasive device with sufficient accuracy, precision andrepeatability to image or analyze targets or to measure analyteconcentrations, and in particular to measure glucose concentration inhuman tissue.

SUMMARY OF THE INVENTION

The invention provides a method, apparatus and system for a non-invasiveimaging and analysis suitable for measuring concentrations of specificcomponents or analytes within a target, such as the concentration ofglucose within human tissue and suitable for non-invasive analysis ofdefects or malignant aspects of targets such as cancer in skin or humantissue. The invention includes an optical source and an optical signalprocessing system which provides a probe and a composite reference beam.It includes a micro-mirror array that enables sequentially switchedmirrors having a large physical separation to be switched at high speed,thus avoiding motion artifacts. It also includes a means that appliesthe probe beam to the target to be analyzed, recombines the scatteredprobe beam and the composite reference beam interferometrically andconcurrently acquires information from different locations within thetarget. It further includes electronic control and processing systems.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the non-invasive analysis system accordingto the invention.

FIG. 2A is a more detailed illustration of the multiple referencegenerator.

FIG. 2B is an illustration of an alternative embodiment of a designusing a MEMS device.

FIG. 3A illustrates yet another embodiment involving a beam-splitter amicro-mirror array and a modulating reflective element.

FIG. 3B illustrates yet another embodiment involving two beam-splitters,two modulating reflective elements and a micro-mirror array.

DETAILED DESCRIPTION OF THE INVENTION

Optical coherence tomography is based on splitting the output of abroadband optical source into a probe beam and a reference beam and ofvarying the optical path length of the reference beam to scan thetarget. This imaging and analysis technology has problems andlimitations including problems and limitations related to motionoccurring within the duration of a scan.

The present invention is a novel interferometric approach, whichaddresses these problems and limitations, by concurrently acquiringmultiple meaningful interferometric signals from multiple depths withinthe target, thus avoiding relative motion artifacts. For purposes ofthis invention “concurrently acquiring” includes simultaneouslyacquiring and acquiring at a speed that is significantly higher thanmotion artifacts. Similarly “concurrent” includes “simultaneous” and “athigh speed with respect to motion artifacts” and “concurrently” includes“simultaneously” and “at high speed with respect to motion artifacts”.With the present invention the interferometric information from thedifferent depths within the target can be distinguished from each otherand separated by electronic processing.

The invention involves generating a composite reference beam consistingof multiple beams (or component reference beams) each corresponding to adifferent path length. In addition to corresponding to different pathlengths, at least some components of the composite reference beam arealso modulated in a different manner to allow the interferometricinformation corresponding to different component reference beams to beseparated by electronic processing. This enables a compact imaging andanalysis system which can concurrently acquire and analyze informationfrom different depths within a target and thereby avoid undesirablemotion related artifacts.

A preferred embodiment of this invention is illustrated in and describedwith reference to FIG. 1 where a non-invasive optical analysis system isshown. The analysis system includes an optical processing system thatgenerates a probe beam and a reference beam from a broadband opticalsource 101, such as a super-luminescent diode or a mode-locked laser,whose collimated output 102, consists of a broad band, discrete orcontinuous, set of wavelengths.

The output beam 102, is passed through a beam splitter 103, to form aprobe beam 104 and a reference beam 105 (which also becomes thecomposite reference beam on its return path). The probe beam 104 passesthrough an optional focusing lens 106. The focusing probe beam 108 isdirected by an optional angled mirror 109 and applied to the target 110below the angled mirror.

At least part of the radiation of the beam applied to the target isscattered back and captured by the lens 106 to form captured scatteredprobe radiation. Scattering occurs because of discontinuities, such aschanges of refractive index or changes in reflective properties, in thetarget. The captured scattered probe radiation passes through the lens106 back to the beam splitter 103.

The reference beam 105 is applied to a composite reference generator 111(which is illustrated in more detail in FIG. 2) where multiplecomponents reference beams are generated that each are related todifferent depths within the target. component reference beams related todifferent depths are modulated in a different manner, such thatinterferometric information can be detected which relates to differentdepths within the target and can be separated by electronic processing.This provides a mechanism for concurrently analyzing information fromdifferent depths within the target, thereby avoiding motion artifacts.

At least a part of the component reference beams are re-combined to formthe generated composite reference beam which returns along the path ofthe reference beam 105 and is referred to as a composite reference beam.The reflected re-combined reference beam, or composite reference beam,is combined interferometrically with the captured scattered proberadiation in the beam splitter 103. (Although typically referred to as abeam splitter the optical element 103 also operates as an opticalcombining element, in that it is in this element that reflectedre-combined reference beam and captured scattered probe radiationcombine interferometrically.) The resulting composite interferencesignal 107 is detected by the opto-electronic detector 112 to form acomposite electronic signal.

A meaningful interferometric signal only occurs with interaction betweenthe reference beam and light scattered from a distance within the targetsuch that the total optical path lengths of both reference and probepaths are equal or equal within the coherence length of the opticalbeam. In this preferred embodiment concurrent information from differentdepth locations is acquired either simultaneously or with time delaythat is small compared to any motion related to the target or componentswithin the target.

The preferred embodiment also includes an electronic processing module,113, which interacts with an electronic control module 114 by means ofelectronic signals 115. The control module 114 provides timing signals,included in signals 115, to provide the electronic processing module 113with timing signals to assist the processing module with filtering andprocessing the detected composite interferometric signals. The controlmodule 114 also generates control and drive signals for the system,including signals 116 to control and drive the optical source andsignals 117 which modulate and control various aspects of the compositereference generator 111.

A preferred embodiment of composite reference generator 111 isillustrated in more detail in FIG. 2, where a MEMS(Micro-Electro-Mechanical System) mirror array is used to generate thecomposite reference beam. In this illustration, the reference beam 201corresponds to the reference beam 105 of FIG. 1. The reference beam 201is routed through a set of switchable micro mirrors, one of which 202 isshown in a position to reflect all or part of the reference beam 201.Other switchable micro mirrors, such as 203 are shown in a nonreflecting position. An optional modulating reflective element 204 canprovide a component of the composite reference signal.

Individual micro mirrors, such as 214 or 215 can be rapidly switched inand out of the reference beam. The speed with which the micro mirrorscome into the reflective position can be used to determine the frequencycontent of the resulting interferometric signal or the micro-mirrorarray unit 205 could be translated to generate a specific frequencycontent. An effective long physical scan can be accomplished byswitching into reflective positions micro mirrors that have a largephysical separation, thus avoiding the requirement of a long physicalscan.

Many configurations are possible, for example, switching of widelyseparated mirrors can be done simultaneously but at different speeds toallow the resulting interferometric signals to be separable by filteringin the electronic domain, or switching can occur one mirror at a timeand the signal used in conjunction with the signal simultaneouslyavailable from the modulating reflective element 205 to determinerelative depth information, or in yet another configuration, switchingcould occur one mirror at a time but at high speed (concurrently) andwith sequentially switched mirrors having a large physical separation,thus avoiding motion artifacts.

The resulting composite reference signal generates interference signalswhen combined with the captured scattered probe radiation. The resultinginterference signals can be separated in the electronic domain bydigital electronic processing involving various combinations of highspeed sequential signal sampling in the time domain and electronicfiltering. Many variations of the multiple reference generator arepossible. For example, in FIG. 2B and additional modulated partiallyreflective element 206. Signals from the partially reflective element206 or the modulating reflective element 205 could be continuouslyavailable and used to locate reference surfaces in the target and toposition the analysis system with respect to them.

Alternatively the modulating signals applied to the modulated partiallyreflective element 206 or the modulating reflective element 205 andindividual micro-mirrors could be switched on one at a time, but at highspeed (concurrently) thereby avoiding motion artifacts, but with theadvantage of only having to process one set of frequency content at atime. Again sequentially switched (closely switched in time)micro-mirrors can have a large physical separation but enable acquiringinformation over a large physical range in a manner that is insensitiveto motion artifacts.

The micro-mirror array can have a large number of micro-mirrors of theorder of thousands which can span a physical distance of the order ofmilli-meters. The ability to switch physically distant mirrorsconcurrently (either simultaneously or within a short time period)enables acquiring sets of information that are insensitive to motion.This motion insensitive information can be processed to analyze or imagethe target. Analyzing such acquire information of targets can provideinformation relating to the concentration of components within thetarget, for example, to determine the concentration of components oranalytes, such as glucose, within the tissue or to generate an image ofthe target.

An alternative embodiment of the composite reference generator isillustrated in FIG. 3A, where there are separate optical paths for themodulating reflective element and the micro-mirror array. In thisillustration, the reference beam 301 corresponds to the reference beam105 of FIG. 1 and is applied to a beam-splitter 302. A portion 303 ofthe reference beam is reflected by the modulating reflective element 304to the beam splitter 302. Another portion 305 of the reference beam isapplied to the micro mirror array 306 as described before.

Many variations involving techniques and configurations are described inthe U.S. utility application Ser. No. 11/025,698 filed on Aug. 19, 2004titled “A Multiple Reference Non-Invasive Analysis System”, whosecontents are incorporated by reference as if fully set forth herein andin the patent application Ser. No. 10/949,917 referenced by andincorporated into this application. For example, multiple modulatingreflective elements separated by additional beam-splitters; phasemodulators or piezo devices could be used to modulate these elements.

Another such possible configuration is illustrated in FIG. 3B which issimilar to the configuration in FIG. 3A in many respects, but has anadditional beam-splitter 307 separates the reference beam 308 into twoportions which are applied to modulating reflective elements 309 and310. The path lengths to these elements 309 and 310 may, for example, beselected to correspond to the approximate locations of known surfaces inthe target. Conventional feedback position control systems could be usedto lock on to these locations and thereby align the analysis system.

For purposes of this invention a source of broadband optical radiation,includes but is not limited to, optical sources of, such as SLDs,mode-locked laser, LEDs, other regions of the electromagnetic spectrum.

It is understood that the above description is intended to beillustrative and not restrictive. Many of the features have functionalequivalents that are intended to be included in the invention as beingtaught. Many of the features have functional equivalents that areintended to be included in the invention as taught. For example, theoptical source could include multiple SLDs with either over-lapping ornon-overlapping wavelength ranges, or, in the case of a mode-lockedlaser source could be an optically pumped mode-locked laser, it could bea solid state laser, such as a Cr:LiSAF laser optically pumped by adiode laser.

The optical source could be an actively mode-locked laser diode or apassively mode locked by a Kerr lens or a semiconductor saturableabsorber mirror. Gain switched optical sources, with optical feedback tolock modes may also be used. For purposes of this invention, mode-lockedlasers will include gain switched optical sources. The optical sourcecould be a VCSEL (vertical cavity surface emitting laser), or an LED(light emitting diode) or an incandescent or fluorescent light source orcould be arrays of the above sources.

Other examples will be apparent to persons skilled in the art. The scopeof this invention should be determined with reference to thespecification, the drawings, the appended claims, along with the fullscope of equivalents as applied thereto.

1. A method for non-invasive analysis of a target comprising: generatinga probe beam and a reference beam; separating the reference beam intomultiple component reference beams; modulating at least some of themultiple component reference beams; re-combining at least part of someof the multiple component reference beams to form a composite referencebeam; applying the probe beam to the target to be analyzed; capturing atleast part of said probe beam scattered from within the target to formcaptured scattered probe radiation; combining the captured scatteredprobe radiation and the composite reference beam; detecting theresulting composite interferometric signal to form a compositeelectronic signal; separating the composite electronic signal intosignals related to concurrent information from different locationswithin the target; and processing said concurrent information to achievenon-invasive analysis of the target.
 2. The method of claim 1, whereinthe probe and reference beams are generated by at least onesuper-luminescent diode.
 3. The method of claim 1, wherein the probe andreference beams are generated by at least one source of broadbandradiation.
 4. The method of claim 1, wherein the reference beam isseparated into component reference beams by at least one beam-splitter.5. The method of claim 1, wherein the reference beam is separated intocomponent reference beams by a partially reflective element.
 6. Themethod of claim 1, wherein the reference beam is separated intocomponent reference beams by a MEMS based mirror array.
 7. The method ofclaim 1, wherein at least one component reference beam is modulated bythe motion of at least one micro-mirror of the MEMS based mirror array.8. The method of claim 1, wherein at least one component reference beamis modulated by sequentially switching micro-mirrors at least some ofwhich have a large physical separation.
 9. The method of claim 1,wherein at least one component reference beam is modulated by the motionof the MEMS based mirror array.
 10. The method of claim 1, wherein atleast some of the different component reference beams are modulated in amanner that results in interferometric signals with different frequencycontent.
 11. The method of claim 1, wherein at least some of thedifferent component reference beams are modulated in a manner thatresults in interferometric signals that occur at different timeintervals.
 12. The method of claim 1, wherein the signals related todifferent component reference beams are separated by electronicprocessing of the detected composite electronic signal.
 13. The methodof claim 1, wherein the concurrent information from different locationswithin the target is processed to provide scattering information. 14.The method of claim 13, wherein the scattering information is analyzedto determine a measurement of an analyte.
 15. The method of claim 14,wherein the measurement of an analyte is the concentration level ofglucose in tissue.
 16. The method of claim 1, wherein the concurrentinformation from different locations is analyzed to provide imaginginformation.
 17. A system for non-invasive analysis of a target, saidsystem comprising: means for generating a probe beam and a referencebeam; means for separating the reference beam into multiple componentreference beams; means for modulating at least some of the multiplecomponent reference beams; means for re-combining at least part of someof the multiple component reference beams to form a composite referencebeam; means for applying the probe beam to the target to be analyzed;means for capturing at least part of said probe beam scattered fromwithin the target to form captured scattered probe radiation; means forcombining the captured scattered probe radiation and the compositereference beam; means for detecting the resulting compositeinterferometric signal to form a composite electronic signal; means forseparating the composite electronic signal into signals related toconcurrent information from different locations within the target; andmeans for processing said concurrent information to achieve non-invasiveanalysis of the target.
 18. An apparatus for non-invasive analysis of atarget, said apparatus comprising: means for generating a probe beam anda reference beam; means for separating the reference beam into multiplecomponent reference beams; means for modulating at least some of themultiple component reference beams; means for re-combining at least partof some of the multiple component reference beams to form a compositereference beam; means for applying the probe beam to the target to beanalyzed; means for capturing at least part of said probe beam scatteredfrom within the target to form captured scattered probe radiation; meansfor combining the captured scattered probe radiation and the compositereference beam; means for detecting the resulting compositeinterferometric signal to form a composite electronic signal; means forseparating the composite electronic signal into signals related toconcurrent information from different locations within the target; andmeans for processing said concurrent information, wherein said means forprocessing said concurrent information enables non-invasive analysis ofthe target.
 19. The apparatus of claim 18, wherein the probe andreference beams are generated by at least one super-luminescent diode.20. The apparatus of claim 18, wherein the probe and reference beams aregenerated by at least one source of broadband radiation.
 21. Theapparatus of claim 18, wherein the reference beam is separated intocomponent reference beams by at least one beam-splitter.
 22. Theapparatus of claim 18, wherein the reference beam is separated intocomponent reference beams by a partially reflective element.
 23. Theapparatus of claim 18, wherein the reference beam is separated intocomponent reference beams by a MEMS based mirror array.
 24. Theapparatus of claim 18, wherein at least one component reference beam ismodulated by the motion of at least one micro-mirror of the MEMS basedmirror array.
 25. The apparatus of claim 18, wherein at least onecomponent reference beam is modulated by sequentially switchingmicro-mirrors at least some of which have a large physical separation.26. The apparatus of claim 18, wherein at least one component referencebeam is modulated by the motion of the MEMS based mirror array.
 27. Theapparatus of claim 18, wherein at least some of the different componentreference beams are modulated in a manner that results ininterferometric signals with different frequency content.
 28. Theapparatus of claim 18, wherein at least some of the different componentreference beams are modulated in a manner that results ininterferometric signals that occur at different time intervals.
 29. Theapparatus of claim 18, wherein the signals related to differentcomponent reference beams are separated by electronic processing of thedetected composite electronic signal.
 30. The apparatus of claim 18,wherein the concurrent information from different locations within thetarget is processed to provide scattering information.
 31. The apparatusof claim 30, wherein the scattering information is analyzed to determinea measurement of an analyte.
 32. The apparatus of claim 31, wherein themeasurement of an analyte is the concentration level of glucose intissue.
 33. The apparatus of claim 18, wherein the concurrentinformation from different depth locations is analyzed to provideimaging information.